This application claims benefit of U.S. Provisional application Ser. No. 60/389,491, filed Jun. 19, 2002.
The present applicant serendipitously and unexpectedly discovered a therapy system useful for treating cancer, AIDS, cardiovascular diseases, Down syndrome, chronic inflammatory diseases, diabetes, neurodegenerative diseases and other disease states mediated by oxidative stress. This system comprises the delivery to the gut of a mammal of therapeutically effective amounts of one or more of the following active agents: sulfide compounds, thiosulfate compounds, thionite compounds, thionate compounds, and any organic, inorganic or organometallic precursors thereof.
The present applicant found in a preliminary evaluative clinical trial with far-advanced human cancer patients having histologically verified malignancies representing a wide range of cancer types (breast, colon, lung, prostate, larynx, testis, uterus, pancreas, muscle lymphoma, including lymphoma in the leg or gluteal muscles, carcinoma, sarcoma.) that a significant rate and extent of reduction in tumor size occurred, often followed by complete remission. The therapy system of the present invention substantially avoids several of the well-known problems and limitations of conventional cancer chemotherapy such as development of resistant malignant-cell variations, excessive concomitant toxicity, dependence on phase of cell cycle and mutagenic side effects.
In other preliminary clinical trials, the present applicant surprisingly found clear evidence of the effectiveness of essentially the same therapy system when applied to patients afflicted with Down syndrome, hypercholesterolemia and cardiovascular disease.
Although sulfur compounds have a long history of pharmaceutical usefulness, only two of the sets of compounds claimed in this application (thiosulfates and sulfites) have found wide use in pharmacology and/or in the formulation of final dosage forms as preservatives, antioxidants, or biocides. Thus, thiosulfates find application in the treatment of cyanide poisoning, allergic conditions and drug sensitization caused by gold, arsenic, mercury or bismuth preparations in humans, and in veterinary medicine as cyanide antidotes, as “general detoxifiers” and also in bloat and, externally, in treatment of ringworm or mange. Injection of aqueous solutions of sodium thiosulfate and L-cysteine or its sodium salt are claimed to be effective against “bacteria and viruses” in general. U.S. Pat. No. 4,148,885, issued to Renoux et al., discloses use of sodium thiosulfate and sodium metabisulfite as immunostimulants, but strictly within the context of “a process for stimulating the immunity of a living organism”, although only mice are mentioned and only subcutaneous administration was employed.
Sulfites also display some pharmacological activity against the agents responsible for certain parasitic and infectious conditions. In addition German patent DE 3,419,686 discloses sulfite or bisulfite solutions for treating arthritis or epilepsy. PCT International Application WO 84/02527 claims increased anti-tumor activity for adriamycin and daunomycin with the addition of sulfites, acid sulfites, pyrosulfites and/or dithionites. U.S. Pat. No. 5,045,316, issued to Kaplan, claims that a combination of an ionic vanadium compound, a thiosulfate or sulfite, and optionally selenium is useful for treating malignant tumors, atherosclerosis and mental syndromes in the elderly. However, it should be clear that in the prior art neither thiosulfates nor sulfites have been claimed to act as herein disclosed by themselves or in admixture with each other and/or with sulfide compounds, thionite compounds, or thionate compounds, when delivered to a mammal in need thereof.
It should also be appreciated that both thiosulfates and sulfites are rapidly decomposed when released in the stomach, so that oral administration of aqueous solutions, tablets, or capsules containing sulfites or thiosulfates cannot be used for their delivery to the gut of a mammal, unless an enteric coating or an ad-hoc delivery system is employed. Exactly the same considerations apply to dithionites, which have been used (see above) in combination with adriamycin and daunomycin. On the other hand, sulfide compounds and thionate compounds have been, to the best of the present applicant's knowledge, neither claimed to act as herein disclosed nor hypothesized to be capable of such action when delivered to a mammal.
Without intending to be bound by any particular hypothesis or theory, current thinking on the etiology of cancer, AIDS, cardiovascular diseases, diabetes, Down syndrome, chronic inflammatory diseases and neurodegenerative disorders will be reviewed, in an attempt to understand the basis for the surprising success of the treatment method disclosed herein. Since the diverse sulfur compounds found by the present applicant to be pharmacologically active all possess reducing properties, special attention will be given to the possibility that a link exists between the two sets of properties and to research that bears on oxidation-reduction processes in cells, especially if it focuses on oxidative stress or its pathological manifestations.
In healthy human tissue a delicate balance between cell proliferation and cell death exists, which when disrupted can lead to a degenerative disease (diabetes and its vascular complications, anemia, arthritis, Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis [A.L.S.], Huntington's disease, muscular dystrophy, myotonic dystrophy, chronic fatigue syndrome, Friedreich's ataxia, ocular lens opacification, nephrosis, liver necrosis, dermatitis, pulmonary immune deficits, hepatic encephalopathy, macular degeneration, age-associated memory impairment, Creutzfeldt-Jacob's disease, stroke, epilepsy, peripheral neuropathy, optic neuropathy, anatomic neuropathy, Neutrogena bowel disease, sensorineural deafness, neurogenic bladder dysfunction, migraine, renal tubular acidosis, dilating cardiomyopathy, hepatic failure, lactic acidemia, arsenic poisoning, silicosis, acetaminophen poisoning, asbestosis, asthma, rheumatic polyarthritis, ARDS adult respiratory distress syndrome) in case of premature cell loss. Similarly, disruption of this balance can lead to a hyperproliferative disease (cancer, AIDS, herpes simplex virus-1 infection, cytomegalovirus-induced vascular pathology, arteriosclerosis, ARC, hepatitis, trypanosomiasis, vascular restenosis, psoriasis, glomerular nephritis, transplant rejection, etc.) in case of cell over-accumulation. It must be pointed out that mitochondrial function is the key to this balance, since mitochondria regulate apoptosis, the physiological mechanism for the elimination of cells in a controlled and timely manner.
The defense mechanism of a mammal (humoral/cellular immunity mediated by non-phagocytic lymphocytes, phagocytic polymorphonuclear leucocytes, and voraciously phagocytic monocytes/macrophages) eliminates foreign bodies such as microorganisms (bacteria, rickettsias, viruses, fungi, protozoa or metazoa) and abnormal cells, including neoformed cells capable of becoming a cancerous tumor such as a carcinoma, sarcoma, myoma or lymphoid tumor through hyperproliferation.
Cancerous tumors are usually life-threatening; in humans they include, among others, prostate, colon, breast, lung, kidney, liver, lymphoma of the central nervous system (CNS), leukemia, pancreatic, gastric, esophageal, ovarian, uterine, testicular and skin tumors. Most human and animal cancer involves cells of epithelial origin, whose malignant transformation results in carcinomas, i.e., tumors of epithelial cell origin.
The balance between cell proliferation and cell death in a healthy mammal depends critically on both an intact immune system, and a finely tuned systemic balance between antioxidants and oxidants, which will be referred to hereinafter as “redox homeostasis”. Moreover, redox homeostasis is also essential for the components of the immune system to function adequately.
Stepwise reduction of molecular oxygen (dioxygen) to water inside mammalian cells is the source of the ATP needed by the cell to power its multiple activities. However, the partially reduced intermediates formed during this process (superoxide radical anion, hydrogen peroxide, hydroperoxy radical and hydroxy radical) are highly reactive and their leakage can be the cause of oxygen toxicity, oxidative stress, and/or oxidative damage to biomolecules and complex cell structures such as membranes and mitochondria; these partially reduced species are known collectively as “reactive oxygen intermediates” (R.O.I.).
Furthermore, some cells belonging to the immune system generate hypochlorous acid or R.O.I.'s (“respiratory burst”) in order to use them as weapons against foreign bodies. Detoxication of xenobiotics (including drugs) is another common source of R.O.I.'s, as well as the enzymatic synthesis of prostaglandins, thromboxanes, and leukotrienes from polyunsaturated fatty acids in epithelial cells.
During the last decade, it has become evident that R.O.I.'s perform an extremely important direct role in signal transduction; most sources of the R.O.I.'s involved in signal transduction seem to initially generate superoxide, whose disproportionation then yields hydrogen peroxide. As noted by Powis et al. (“Redox signaling and the control of cell growth and death”, in Helmut Sies (ed.) “Antioxidants in disease mechanisms and therapy”, Academic Press, 1997), intracellular redox signaling is the result of controlled changes in the intracellular redox state. This signaling can regulate the cell cycle, including the control of DNA synthesis, enzyme activation, and gene expression. The redox signaling operates by changing the conformation of key proteins by changing the oxidation state of cysteine residues in these proteins. These conformational changes affect the biological function of the protein. These conformationally sensitive proteins directly affect cell growth and differentiation, as well as cellular apoptosis.
A variety of experimental results, reported between 1994 and 2000, illustrate the importance of redox status/R.O.I.'s in cellular signaling systems and mammalian health. Metallothionein-III (MT-III) is a brain-specific metallothionein, which is markedly reduced in the brain of patients with Alzheimer's disease (AD) and other degenerative diseases. Oxidative stress seems to be one of the principal factors that modulate MT-III mRNA (Messenger Ribonucleic Acid) expression. Pulmonary surfactant, a mixture of phospholipids and surfactant proteins (SP-A and SP-B) reduces surface tension at the air-liquid interface and protects the large epithelial surface of the lung from infectious organisms. Cellular oxidants reduce surfactant protein expression. Also, antioxidants reduce cyclooxygenase-2 expression, prostaglandin production and proliferation in colorectal cancer.
Overexpression of mdr-1 type transporters in tumor cells contributes to multidrug-resistance. The induction of mdr-1bmRNA and of functionally active mdr1-type P-glycoprotein by elevation in intracellular levels of reactive oxygen species and the repression of intrinsic mdr-1bmRNA and P-glycoprotein overexpression by antioxidants support the conclusion that the expression of the mdr-1b P-glycoprotein is regulated in a redox-sensitive manner.
Oxidative stress regulates the expression of various regulatory genes in rabbit lens epithelial cells, which likely affects cell proliferation, differentiation, and viability and thus affects normal cell function [CA 127:230414h].
In cultured keratinocytes, Butylated Hydroxytoluene Hydroperoxide (BHTOOH) stimulates a time-dependent increase in ornithine decarboxylase (ODC) enzyme activity paralleled by induction of ODCmRNA (mRNA that directs ODC synthesis), suggesting transcription regulation of ODC by BHTOOH. Depletion of intracellular glutathione caused a 5-fold potentiation of keratinocyte sensitivity to BHTOOH and consequently, of tumor promotion.
R.O.I.'s can also act indirectly as signal transducers by modifying the bioavailability of nitric oxide (NO); thus, inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) and interleukins (IL's) induce NO (nitric oxide) overproduction. NO is a messenger endogenously synthesized by a variety of mammalian cells including neurons, smooth muscle cells, macrophages, neutrophils, and platelets. In fact there is cross-talk between R.O.I.'s and NO, since the effects of the latter are influential on signaling pathways regulated by thiolic redox status.
However, if superoxide and NO interact a powerful non-radical oxidant, peroxynitrite (PN), is readily formed. PN is capable of oxidizing a number of biomolecules and complex cell structures including enzymes such as catalase and glutamine synthetase, proteins containing tyrosine residues, DNA, brain mitochondria and membrane lipids such as synaptosomal membranes.
NO itself has been implicated in a variety of neurodegenerative disorders and is a mediator in excitotoxic and post-hypoxic damage to neurons. DNA strand breakage is induced synergistically by NO and a catecholamine.
Most living organisms have evolved well-integrated antioxidant defense mechanisms, which include both antioxidant enzymes such as catalase, superoxide dismutases, glutathione peroxidases, quinone reductase, diaphorase and ceruloplasmin and low molecular weight antioxidants (LMWAO's) such as pyruvic acid, glutathione (GSH), dihydrolipoic acid (DHLA), beta-carotene, vitamin C, vitamin E and thioredoxin (TRX, a ubiquitous, relatively small, dithiolic, hydrogen-carrier protein).
Whereas antioxidant vitamins and beta-carotene must be supplied through food intake (e.g. in fruits and vegetables), both the thiolic tripeptide glutathione and DHLA are endogenous antioxidants, as well as pyruvic acid.
Pyruvic acid, being a normal tissue metabolite, is likely to be non-toxic and its high effectiveness as a “peroxide scavenger” is well documented; furthermore, after scavenging hydrogen peroxide or organic hydroperoxides it is converted into acetic acid, which means that it is intrinsically incapable of acting as a prooxidant. In spite of these attributes, pyruvic acid's role as an endogenous antioxidant has been widely underestimated: it is probably an important but underrated contributor to the “redox buffering” capacity of blood serum.
Glutathione (L-gamma-glutamyl-L-cysteinylglycine) is a ubiquitous intracellular thiol present in almost all mammalian tissues; the liver has very high intracellular levels of GSH.
Besides maintaining cellular integrity by enforcing a reducing environment, GSH has multiple functions including detoxication of xenobiotics; synthesis of proteins, nucleic acids, leukotrienes, prostaglandins and thromboxanes through its action as a coenzyme; and preventing other antioxidants from becoming pro-oxidants.
GSH enforces a reducing intracellular environment by acting as an excellent scavenger of both oxygen-centered and nitrogen-centered free radicals (reactive nitrogen intermediates, RNIs) and by readily converting non-radical oxidants (PN, peroxides, hydroperoxides) into harmless compounds. After acting as a coenzyme or scavenging R.O.I.'s or PN, GSH is oxidized to GSSG (glutathione disulfide), from which GSH is regenerated enzymatically. The redox system of GSH consists of primary and secondary antioxidants, including glutathione peroxidases, glutathione reductase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase.
Redox reactions in which GSH plays a role include protein folding, conversion of ribonucleotides to desoxyribonucleotides, and maintenance of reduced pools of vitamins C and E; GSH can also undergo reversible thiol-disulfide exchange with proteins containing oxidized cysteine (i.e., cystine) residues.
Whereas in tissues and red blood cells (CA 131:156247v) GSH is the foremost “redox buffer”, in blood plasma this function has been assigned to albumin, although this applicant believes that pyruvic acid is also a key antioxidant in both environments.
As stated above, DHLA and thioredoxin perform roles that complement those of GSH; their oxidized forms can also be reduced easily by enzyme action. Vitamins C and E, which can readily and reversibly act as hydrogen donors as well, also contribute to maintain the intracellular oxidant-reductant balance (redox homeostasis).
By operating in a concerted and often synergistic manner, the redox mediators GSH, DHLA, TRX, Vitamin C, Vitamin E, and the antioxidant enzymes help maintain a reducing intracellular environment. This reducing environment performs a variety of important cellular functions. First, it helps keep bioactive quinones in the reduced state. For example, cardiotonic ubiquinones and vitamin K are maintained in their reduced state (ubiquinol/hydroquinone), so as to minimize the probability of arylating DNA and of generating R.O.I.'s in anaerobic or aerobic conditions. Also, it keeps catecholamines (adrenaline, dopamine, etc.) in the reduced (hydroquinone) condition, preventing their irreversible oxidation to quinoneimines of the adrenochrome type. The reducing intracellular environment also prevents vasoactive serotonin from being oxidized to a reactive quinoneimine.
The reducing intracellular environment prevents inactivation of heart dihydrolipoamide dehydrogenase and of other oxidant-sensitive enzymes such as glutamine synthetase. The reducing environment attenuates hypersensitivity responses induced by oxidative activation of phenolic haptens, and preserves the functional integrity of the blood-brain barrier, of the intestinal epithelium, and of the heart endothelium. It also helps preserve cytoskeletal integrity. The reducing environment protects synaptosomal membranes from oxidation, and prevents the death of hippocampal neurons. It is also important to phagocytes, as it supports their random migration, chemotaxis, ingestion and superoxide production.
Of particular significance is the role of a reducing environment in preserving the functional integrity of mitochondria. GSH and Glutathione peroxidase (GPx) play a critical role here, since mitochondria lack catalase, an enzyme which degrades hydrogen peroxide. “Mitochondrial diseases” are disorders to which deficits in mitochondrial respiratory chain activity contribute. This category includes deficiencies in the activity of components of the mitochondrial respiratory chain. Typically, these deficiencies are caused by exposure of the cells to nitric oxide and hypoxia or ischemia or oxidative stress on the tissue. These deficiencies in antioxidants or antioxidant enzymes can result in or exacerbate mitochondrial degeneration. It must be pointed out that redox homeostasis also requires a delicate antioxidant enzyme balance in cells: too much Superoxide Dismutase (SOD) relative to GPx or catalase results in the accumulation of hydrogen peroxide, which in turn, through the Fenton reaction, leads to the production of hydroxyl radical and concomitant cell damage; however, too little SOD enzyme is also not favorable because superoxide radicals in themselves are toxic to cells. Therefore, fine-tuning of the antioxidant enzymes. (together with the nonenzymatic antioxidants) becomes imperative if the cell is to function successfully in an oxygen-rich environment.
Down syndrome is believed to be the consequence of a congenital perturbation in the balance of antioxidant enzymes, with damage to important biomolecules brought about by a highly pro-oxidant intracellular environment.
In the face of stresses such as injury or infection, organisms rapidly marshal a host of responses: immune cells are recruited and various genes are rapidly activated. The key coordinating factor in this activation is the nuclear transcription factor NF-κB, which also plays a crucial role in modulating gene expression during growth and development.
Among the genes modulated by NF-κB are those encoding cytokines (TNF-α, IL's, etc.) and growth factors, immunoreceptors, adhesion molecules, acute-phase proteins, other transcription factors and regulators, NO-synthase, and viral genes. Most target genes for NF-κB are intrinsically linked to a coordinated inflammatory response.
NF-κB has far-reaching significance for a variety of pathological conditions in which inflammation, growth, or viral activation occur, such as tumor genesis, HIV infection (AIDS), atherosclerosis, diabetes, rheumatoid arthritis, chronic bronchitis, cystic fibrosis, idiopathic pulmonary fibrosis, ARDS, septic shock, cirrhosis, ulcerative colitis, reperfusion injury, inflammatory bowel disease, pulmonary emphysema, neurodegenerative disorders, (Alzheimer's Disease, Parkinson's Disease, etc.), osteoporosis, asthma, renal disease, rheumatoid synovitis, and the animal model of multiple sclerosis, experimental allergic encephalomyelitis.
An important NF-κB regulated gene is that encoding the cytokine TNF-α which plays a central role in several inflammatory conditions. Since TNF-α is itself an activator of NF-κB, the potential for a positive inflammatory feedback cycle with disastrous consequences can be envisioned.
As stated above, the activation of NF-κB has been implicated in a wide range of diseases in which there is an inflammatory and/or hyperproliferative component including AIDS, where the expression of HIV is NF-κB dependent. It is now clear that ROI/RNI are mediators of NF-κB activation, and also that this process can be blocked by antioxidant agents.
Antioxidant agents can also inhibit the production of TNF-α. Excessive or unregulated TNF-α production mediates or exacerbates a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, Adult Respiratory Distress Syndrome (A.R.D.S.), cerebral malaria, chronic pulmonary inflammatory disease, silicosis, asbestosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, AIDS related complex, keloid formation, scar tissue formation, Cohn's disease, ulcerative colitis, pyrosis and fever and myalgias due to infection.
Although most experts would admit the possibility that “the time course and even the final outcome, of a disease can be critically modulated by strengthening the antioxidant side of the balance between prooxidants and antioxidants, it is unfortunately true that single antioxidants as pharmacologically active agents have not been found to exhibit extremely powerful therapeutic effects. For example, the jury is still out regarding the effectiveness of vitamin C as a therapeutic agent. Nevertheless, vitamin C may have a role in impeding the progress of diabetes, cataract, heart disease, cancer, aging, and a variety of other disease states. Several methods for modulating cellular GSH levels in human diseases associated with GSH deficiency and oxidative stress are still being evaluated. DHLA, regarded in some quarters as a unique “ideal” antioxidant remains an intriguing possibility for the treatment of conditions (notably AIDS, atherosclerosis and diabetes) related to oxidative stress.
Treatment of severe vitamin E deficiency with appropriate supplements of the vitamin can at least halt the progression of the characteristic neurological features, but in the majority of clinical neurological conditions the therapeutic benefits of antioxidant supplementation still requires to be proved. On the other hand, vitamin E has been reported to regress oral leukoplakia (a precancerous lesion). Supplemental beta-carotene reduces the frequency of “oral micronuclei” (an indicator of genotoxic damage to the oral epithelium) significantly; it is also effective against oral leukoplakia. Preliminary results of studies on pre-cachectic and cachectic HIV-infected patients indicate that the decrease of plasma cystine, glutamine, and arginine levels can be corrected by N-Acetyl-L-Cysteine (NAC). Anecdotal data also suggest that this strategy may slow or even prevent the progression of the disease.
A preliminary report indicates that ARDS patients receiving NAC (po [by mouth]), □-tocopherol (po), selenium (iv.[intravenous]), and ascorbic acid (iv.) within 24 hrs. of diagnosis for 3 days experienced a significant reduction in mortality (n=25; 20% mortality) compared to a control group (n=20; 65% mortality); however, these results are in need of validation.
Finally, a randomized trial (n=65) with biopsy-confirmed transitional cell bladder carcinoma patients yielded promising results: the 5-year estimate of tumor recurrence was 91% in the “RDA arm” (patients receiving multivitamins at RDA (Recommended Daily Allowance) levels) vs. 41% in the “megadose arm” (patients receiving multivitamins at RDA levels plus 40,000 IU retinol plus 100 mg pyridoxine plus 2000 mg ascorbic acid plus 4000 IU alpha tocopherol plus 90 mg zinc).
This rather limited success might seem at first surprising in view of the decreased levels of selected major antioxidants consistently found in a number of disease states (GSH in AIDS, hepatitis C, type II diabetes, ulcerative colitis, A.R.D.S., idiopathic pulmonary fibrosis and neurodegenerative syndromes; vitamin E in atherosclerosis, ARDS, Down syndrome and Alzheimer's disease; ascorbic acid in ARDS; beta-carotene in cystic fibrosis; vitamin A in Down syndrome and Alzheimer's disease, etc.). On second thought, however, the limited success of this “magic single antioxidant approach” can be rationalized by recalling that mammals possess highly evolved and well-integrated antioxidant mechanisms which require the concerted and synergistic action of both antioxidant enzymes and low molecular weight antioxidants, with different antioxidants operating extracellularly and/or in specific cell compartments (aqueous vs. lipidic microenvironments) and having limited functional overlap. Some antioxidants destroy peroxidic species and/or PN, others break free radical chains; still others quench singlet oxygen.
There are other foreseeable obstacles in the way of the “single antioxidant” approach to therapy. Several antioxidants have been shown to be capable of acting as pro-oxidants or as NF-κB activators “in vitro” and/or “in vivo” under rather specific conditions, including ascorbic acid, beta carotene, glutathione, flavonoids, NAC, and L-cysteine. Limited evidence suggests that administration of a single antioxidant might have adverse effect(s) on plasma levels of other antioxidants.
After this appraisal of the current biochemical research on the etiology of cancer, AIDS, cardiovascular diseases, diabetes, Down syndrome, neurodegenerative disorders and chronic inflammatory diseases, the following hypotheses might help explain the remarkable success of the therapy system herein described:
The sulfur compounds comprised by the therapy system herein disclosed act as inducers of antioxidant enzymes, thereby enhancing the immune system and/or reactivating mitochondria and/or increasing GSH levels, i.e. their effects are similar to those of 1,2-dithiole-3-thiones. The sulfur compounds herein disclosed act as powerful antioxidant enzyme activators. Specifically, they interact chemically, as reductants, with inactivated enzymes containing disulfide bonds which are thereby cleaved and converted into thiol groups with concomitant restoration of enzyme function. In this case their effect would be akin to that of hydrogen sulfide on inactivated (oxidized) papain. The sulfur compounds on which the present invention is based (excepting sulfides and hydrosulfides) act indirectly through the delivery of “reducing equivalents” to cells subject to oxidative stress, their effect being restoration of redox homeostasis and immune function. The mediator might well be pyruvic acid (see above) since it is known that pyruvic acid can act systemically when delivered to the gut; i.e. it can be readily transported from the gut to other tissues. Further, pyruvate has been shown to enhance the endogenous GSH system Also, there is a linear relationship between GSSG-to-GSH and lactate-to-pyruvate ratios in human blood before, during and after exercise.
In a study on the nutritional requirements of human gut sulfate-reducing bacteria, it was found that short-chain fatty acids such as butyric acid, lactic acid, and other organic acids; alcohols; and amino acids (but not sugars or aromatic compounds) stimulated sulfate reduction. Experiments with two strains of desulfovibrio desulfuricans isolated from human feces demonstrated that both were able to reduce sulfite, thiosulfate or nitrate in the absence of sulfate.
Therefore, while the present invention is not to be restricted by any hypothesis, it is possible that pyruvate, synthesized in the gut by bacterial microflora from lactate and sulfite or thiosulfate (or some other sulfur species capable of undergoing reduction), is then transported to the mammal's tissues, wherein it acts, mainly at the mitochondrial level, as a peroxide scavenger and a source of both NADH and energy (via acetyl coenzyme A); NADH (reduced nicotinamide adenine dinucleotide) can enzymatically reduce lipoic acid (LA) to DHLA, which can in turn reduce GSSG to GSH.
Considering the seriousness of the AIDS pandemic, the global burden of cancer (with close to 10 million newly diagnosed cases each year), and the devastating effects of such diseases as diabetes, chronic inflammatory diseases, neurodegenerative pathologies, and Down syndrome it is clear that a pressing need exists for effective treatments of pathological states related to oxidative stress and/or exacerbated or mediated by NF-κB/TNF-α, such as the ones referred to above. This becomes even more clear when we consider the fact that cardiovascular diseases (and atherosclerosis, which is believed to be their underlying primary cause) are the main cause of death in most developed countries.